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Review Article
JulieR. Ingelfinger, M.D., Editor
ew diseases have a greater effect on the health of young children than viral lower respiratory tract illness. Approximately 800,000 children in the United States, or approximately 20% of the annual birth cohort,
require outpatient medical attention during the first year of life because of illness
caused by respiratory syncytial virus (RSV).1 Between 2% and 3% of all children
younger than 12 months of age are hospitalized with a diagnosis of bronchiolitis,
which accounts for between 57,000 and 172,000 hospitalizations annually.1-4 Estimated nationwide hospital charges for care related to bronchiolitis in children
younger than 2 years of age exceeded $1.7 billion in 2009.5 Globally, in 2005, RSV
alone was estimated to cause 66,000 to 199,000 deaths among children younger
than 5 years of age, with a disproportionate number of these deaths occurring in
resource-limited countries.6,7 In the United States, by contrast, bronchiolitis due to
RSV accounts for fewer than 100 deaths in young children annually.8
This review describes the current understanding of bronchiolitis, including the
increasing number of viruses that are known to cause it, the current understanding of its pathogenesis, the importance of environmental and host genetic factors,
and the roles of season, race, and sex in bronchiolitis attack rates and subsequent
episodes of wheezing. In addition, guidelines from the American Academy of Pediatrics regarding the diagnosis, management, and prevention of bronchiolitis are
summarized.9,10
Cl inic a l Fe at ur e s
A young child with bronchiolitis typically presents to a health professional during
the winter months after 2 to 4 days of low-grade fever, nasal congestion, and
rhinorrhea with symptoms of lower respiratory tract illness that include cough,
tachypnea, and increased respiratory effort as manifested by grunting, nasal flaring, and intercostal, subcostal, or supraclavicular retractions.11 Inspiratory crackles
and expiratory wheezing may be heard on auscultation. Various definitions of
bronchiolitis have been proposed, but the term is generally applied to a first episode of wheezing in infants younger than 12 months of age. Apnea, especially in
preterm infants in the first 2 months of life, may be an early manifestation of
viral bronchiolitis.12 Reported rates of apnea among infants with bronchiolitis
range from 1 to 24%, reflecting differences in the definitions of bronchiolitis and
apnea and the presence of coexisting conditions.
The variable course of bronchiolitis and the inability of medical personnel to
predict whether supportive care will be needed often results in hospital admission
even when symptoms are not severe. A variety of potential clinical markers have
been proposed for use in identifying infants who are at risk for severe disease.
Unfortunately, current scoring systems have low power to predict whether illness
will progress to severe complications that would necessitate intensive care or mechanical ventilation.
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Table 1. Viruses Detected in Nasopharyngeal Secretions from Hospitalized Children with Bronchiolitis.*
Virus
Type
Approximate
Frequency
%
A and B
5080
Human rhinovirus
Groups A, B, and C;
>100 serotypes
525
Parainfluenza virus
525
Subgroups A and B
510
Coronavirus
OC43, 229E
NL63, and HKU1
510
Adenovirus
>50 serotypes
510
A and B
15
Echovirus and
coxsackievirus
15
Human metapneumovirus
Influenza virus
Enterovirus
* Viruses are listed in descending order of frequency as a cause of bronchiolitis. Human bocavirus has been detected as
a copathogen in bronchiolitis, but it is isolated infrequently as a single agent in hospitalized children, leading to speculation that this virus is more likely to be an innocent bystander than a true pathogen. No evidence has been found for a
primary role of bacteria as a cause of bronchiolitis, although Bordetella pertussis, Chlamydia trachomatis, or Mycoplasma
pneumoniae may be included in the differential diagnosis of a lower respiratory tract infection in a young child. Coinfection
with viral and bacterial pathogens such as Haemophilus influenzae type b or Streptococcus pneumoniae is uncommon,
mainly because of the widespread use of conjugate polysaccharide vaccines. RSV denotes respiratory syncytial virus.
V ir a l C ause s
The availability of molecular-detection techniques
has made it possible to identify a diverse group
of viruses that are capable of causing bronchiolitis (Table1). Although the reported proportion
of hospitalizations that are attributable to each
virus differs according to the geographic area
and the year, the most common pathogen is RSV,
followed by human rhinovirus. RSV accounts for
50 to 80% of all hospitalizations for bronchiolitis during seasonal epidemics in North America.1-4 Although the clinical features of bronchiolitis due to different viruses are generally
indistinguishable, some differences in the severity of disease have been reported. For example,
it has been observed that rhinovirus-associated
bronchiolitis may result in a shorter length of
hospitalization than bronchiolitis that is attributable to RSV.13 Differences in the response to
medical intervention have not been identified
consistently among children with bronchiolitis
caused by different viruses.
The epidemiologic and clinical importance of
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T-cell response does not develop in such infants is supported by reports of a direct correlation between RSV load, as measured in nasopharyngeal aspirates obtained from children
who have been hospitalized with bronchiolitis,
and more severe disease, defined as a higher
risk of apnea, a longer hospital stay, and a
greater need for intensive care.26,27 However, not
all reports are consistent with an association
between a high viral load in respiratory secretions and greater severity of disease.28-30 A reasonable deduction is that direct cytotoxic injury
induced by the virus and a robust host inflammatory response both contribute to the pathogenesis of RSV bronchiolitis, although the relative contribution of each remains uncertain.
Resolution of this issue will determine whether
a potent antiviral agent administered early in
the course of bronchiolitis can reduce the duration and severity of illness without the need for
immune modulation.
Pathogenesis of RSV
B RO N C H IO LE LU ME N
RSV virion
H E A LT H Y CHILD
Child inhales
droplets
Virus attaches to
and infects the
epithelial cells
E PIT H E LIA L C E LLS
2
Nasopharyngeal cells are sloughed
and aspirated, carrying RSV to
lower respiratory tract cells
Healthy bronchiole
Epithelial cells
BRONCHIOLE
LU MEN
LU NG S
MUCUS
ALV EOLI
Bronchiolitis
Bronchiole
with narrowed
lumen
Debris (mucus,
sloughed cells,
fibrin)
H O S PI T A LIZED
CH I LD
E PIT H E LIU M
Edema
Expanded
alveoli with
trapped air
Obstruction
Obstruction
LU NG S
Edema, cellular
infiltration
compressing
bronchiole
4
Collapsed
alveoli
Loss of
integrity
of alveoli
Absorption of trapped air in the alveoli distal
to the obstruction leads to localized atelectasis
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R isk Fac t or s
Most infants who are hospitalized with RSV
bronchiolitis were born at full term with no
known risk factors.1,2 Chronologic age is the
single most important predictor of the likelihood of severe bronchiolitis, given the observation that approximately two thirds of hospitalizations of infants with RSV infection occur in
the first 5 months of life.1-3 Hospitalization rates
that are attributable to RSV bronchiolitis are
highest between 30 and 90 days after birth, a
period that corresponds to the declining concentration of transplacentally acquired maternal
immunoglobulin.3 Efficient transplacental passage of RSV neutralizing antibody occurs in infants who are born at full term.31,32 Because most
maternal immunoglobulin transfer occurs in the
third trimester, preterm infants may miss the
period of greatest IgG transfer; this fact partly
explains the higher risk of disease among preterm infants.
Children with certain coexisting conditions,
including prematurity (delivery at <29 weeks of
gestation), chronic lung disease of prematurity,
and congenital heart disease, may have more
severe RSV disease than children without such
conditions.10,33 Some studies suggest that the
risk of severe RSV disease is higher among premature infants born before 29 weeks of gestation than among those born at 29 weeks of
gestation or later.1,3,34,35 In contrast, the available
data do not show significantly higher rates of
hospitalization for RSV infection among preterm infants born from 29 to 36 weeks of gestation who do not have chronic lung disease of
prematurity than among full-term infants (delivery at 37 weeks of gestation).3,34,35
Chronic lung disease of prematurity is characterized by alveolar loss, airway injury, inflammation and fibrosis due to mechanical ventilation, and high oxygen requirements.36 Such lung
injury increases the risk of severe bronchiolitis
to a greater extent than does prematurity alone.
Because of the use of antenatal glucocorticoids
and surfactant replacement, improvements in
methods of ventilatory support, and a better
understanding of neonatal nutrition, many preterm infants are healthier at discharge today
than in the past.
Infants born with certain types of hemodynamically important congenital heart disease,
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Bronchiol i t is a nd A s thm a
Severe bronchiolitis early in life is associated
with an increased risk of asthma, especially after
rhinovirus or RSV bronchiolitis, and an increased
risk of asthma may persist into early adulthood.50-52 An unresolved question is whether
bronchiolitis early in life results in injury that
alters normal lung development and predisposes
the child to subsequent wheezing or whether
certain infants have a preexisting aberration of
the immune response or of airway function that
predisposes them to both severe bronchiolitis
and recurrent wheezing.53
Some data support the interesting possibility
that premorbid lung function may be abnormal
among infants who have severe bronchiolitis in
the first year of life.54-57 Pulmonary-function
studies conducted before discharge from the neonatal unit and then repeated after each childs
first RSV season show persistent pulmonary
abnormalities in some infants, regardless of
whether they had bronchiolitis. This finding
suggests that preexisting pulmonary abnormalities are separate from bronchiolitis and not a
complication of it.57 For example, some infants
may have narrow airways when they are well; as
a result, bronchioles are less likely to remain
patent once they become further narrowed by
infection. Confirmation of this possibility would
make it possible to identify infants who would
be most likely to benefit from active or passive
prophylaxis.
A genetic predisposition to severe bronchiolitis
early in life and to the subsequent development
of asthma is supported by reported associations
between polymorphisms in genes involved in the
innate immune response and genes mediating
allergic responses, surfactant proteins, and inflammatory cytokines.58-60 An association between rhinovirus infection early in life and an
increased risk of childhood-onset asthma is associated with genetic variation at the chromosome 17q21 locus.52 The fact that this associa-
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Im munoproph y l a x is
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Table 2. American Academy of Pediatrics Guidance for Diagnosis and Management of Bronchiolitis.*
Intervention
Recommendation
Comment
Chest radiography
Poor correlation with severity of disease or risk of progression; studies show increase in inappropriate
use of antimicrobial therapy owing to similar radiographic appearance of atelectasis and infiltrate
Bronchodilator therapy
Not recommended
Randomized trials have not shown a consistent beneficial effect on disease resolution, need for hospitalization, or length of stay
Epinephrine
Not recommended
Glucocorticoid therapy
Not recommended
May be considered
Nebulized 3% saline may improve symptoms of mildto-moderate bronchiolitis if length of stay is >3
days (most hospitalizations are <72 hr)
Diagnostic Test
Treatment
Supplemental oxygen
Routine use not recommended if oxyhemoglo- Transient episodes of hypoxemia are not associated
bin saturation is >90% in the absence of
with complications; such episodes occur commonly
acidosis
in healthy children
Pulse oximetry
Chest physiotherapy
Not recommended
Antimicrobial therapy
* Adapted from the clinical practice guidelines for the diagnosis and management of bronchiolitis in children 1 through 23 months of age.9
4.8% in the prophylaxis group, P<0.001).23 Recommendations for more restrictive use of passive immunoprophylaxis have evolved since
palivizumab was licensed as additional information has become available regarding the epidemiology of RSV and the limited benefit of prophylaxis. Guidance from the American Academy
of Pediatrics regarding the use of palivizumab is
stratified according to risk, targeting the infants
who are most likely to benefit from prophylaxis.9,10 Table3 presents an overview of the current
guidelines regarding immunoprophylaxis.
F u t ur e Dir ec t ions
RSV is one of the last viruses to cause annual
worldwide outbreaks of disease against which
no safe and effective vaccine is available. Several
approaches to vaccine development are being
investigated.68 A live attenuated vaccine for intranasal administration would stimulate both topical and systemic immunity; such a vaccine is
being developed with the use of reverse genetics
to modify specific genes. Efforts to date have
been hampered by the difficulty of achieving
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Prophylaxis Recommendation
Comment
Born at 29 wk of gestation
Not recommended
No significant difference, as compared with full-term infants, in rate of hospitalization for bronchiolitis3,34,35
Acyanotic disease
Not recommended except for chil- Except for children with chronic lung disease, RSV hos
dren with chronic lung disease
pitalization rates in second year of life are less than
who continue to require supplerates for first 6 mo of life among healthy, full-term
mental oxygen or diuretic or
infants for whom prophylaxis is not recommended34
glucocorticoid therapy
* Guidance for the use of palivizumab for immunoprophylaxis was first provided in 1998.67 It has been revised periodically to reflect ongoing
assessments of peer-reviewed studies regarding the minimal benefit of palivizumab prophylaxis on the hospitalization rate among preterm
infants, the absence of a significant reduction in mortality or the need for mechanical ventilation among RSV-infected children who received
palivizumab as compared with those who received placebo, the enhanced understanding of the pharmacokinetics of palivizumab, the seasonality of RSV circulation in the United States (as shown in data from the Centers for Disease Control and Prevention38), the declining incidence of hospitalization for all-cause bronchiolitis, decreasing mortality among children hospitalized with laboratory-confirmed RSV infection, and data showing clinically minimal or no reduction in wheezing episodes among children who received prophylaxis.62,64
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proach would circumvent the need for vaccination in the first weeks of life, when an infants
immune response is limited.
Until safe and effective vaccines are available,
reduction of the burden of disease due to bronchiolitis will focus on education about the importance of decreasing exposure to and transmission of respiratory viruses. The application
of new forms of technology to the development
of vaccines and antiviral therapies such as fusion
inhibitors and nucleoside analogues may improve the prevention of RSV infection and the
treatment of children with bronchiolitis throughout the world.68,69
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
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